Peritonitis is an inflammation of the internal lining of the abdominal cavity. The most common causes of peritonitis are bacterial infection and chemical irritation. Bacterial peritonitis is usually secondary to bacterial penetration through an abdominal organ as occurs with disorders such as appendicitis, acute cholecystitis, peptic ulcers, diverticulitis, bowel obstruction, pancreatitis, mesenteric thrombosis, pelvic inflammatory disease, tumor or penetrating trauma, or combinations thereof. In addition, spontaneous bacterial peritonitis (SBP) can develop without an obvious source of contamination. SBP is frequently associated with immunosuppressed states, such as cirrhotic ascites or the nephrotic syndrome. Peritonitis is also a common complication of chronic ambulatory peritoneal dialysis (CAPD).
Although virtually every organism has been implicated in bacterial peritonitis, the most common organisms are Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, C. perfingens, Neisseria gonorrhea, Chlamydia trachomatis, Mycobaterium tuberculosis, Chlamydia trachomatis, Clostridium perfringens, streptococci and enteroococci. The most common fungal agents to cause infectious peritonitis are Candida albicans, Candida parapsilasis, and Aspergillus fumigaus. Non-infectious chemical peritonitis can result from foreign materials introduced into the peritoneum, for example, during surgery or by trauma. Chemical peritonitis can also develop in conditions, such as acute pancreatitis, which introduce irritating endogenous materials, such as digestive enzymes or bile, into the peritoneal cavity.
Peritoneal adhesions and abscesses are frequent long-term complications of peritonitis. Peritoneal adhesions are abnormal fibrous tissue connections between intraperitoneal serosal surfaces. Surgery and abdominal inflammation are the most common causes of peritoneal adhesions. Peritoneal infection is often accompanied by peritoneal inflammation, including exudation of fibrinogen and fibrin into the abdominal cavity. The presence of fibrinogen and fibrin promotes fibrosis and adhesion formation.
Inflammation also results in the intraperitoneal accumulation of growth factors, cytokines, proteases, and extracellular matrix which further promotes fibrosis and adhesion formation. In infectious peritonitis, fibrin deposits may trap infectious agents resulting in abscesses, which in turn can cause more fibrous adhesions. Peritoneal adhesions limit the normal motion and function of the intra-abdominal organs, particularly the normal function of gastrointestinal tract. Peritoneal adhesions also can result in pelvic pain, infertility, and ischemic bowel obstructions.
Peritoneal abscesses are walled-off collections of microorganisms and inflammatory cells and mediators (i.e., “pus”). Peritoneal abscesses are difficult to treat because they are walled-off by fibrous capsules making it difficult to achieve therapeutic levels of antibiotics within peritoneal abscesses. Peritoneal abscesses can be the source of serious infections in distant organs, and sepsis. Thus, peritoneal adhesions and abscesses are a major cause of morbidity and mortality. The effective treatment or prevention of peritonitis can significantly reduce the risk of developing intraperitoneal adhesions and abscesses.
The methods currently used for treating or preventing peritonitis are limited. In some cases, chemical peritonitis can respond to irrigation of the abdominal cavity. The use of multiple re-explorations and intra-operative lavage with large amounts of sterile saline solution has been recommended to decrease the risk of post-operative peritoneal infection, peritonitis and adhesions. However, there is still a significant risk of developing peritonitis and adhesions despite the use of repeated lavages with sterile saline. Various topical antimicrobials have also been tested but none has been widely accepted for source control due to either, lack of efficacy or serious side effects (i.e. sclerosing peritonitis). Further, systemic antibiotic therapy is often required, even if the condition is originally chemical in etiology.
Depending on the type and severity of the peritonitis, the clinical picture could progress to an acute systemic inflammatory response syndrome (SIRS), sepsis or septic shock. The physiopathology of these conditions is complex but it can be associated with the presence of infection and of an acute inflammatory reaction both, locally and systemically. Thus, even in early stages (i.e. SIRS), there is accumulation of pro-inflammatory cytokines in the peritoneal cavity and in the blood that contribute to the establishment of multi-organ failure and death. These cytokines, at least in murine peritonitis models, are mostly derived from activated mast cells in the peritoneal cavity.
Accordingly, there is a need for improved methods of treating or preventing peritonitis. The present invention provides such methods. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.